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Inhibition of AMP-activated protein kinase protects pancreatic β-cells from cytokine-mediated apoptosis and CD8+ T-cell-induced cytotoxicity

Riboulet-Chavey, Audrey, Diraison, Frederique, Siew, Lai Khai, Wong, Florence Susan and Rutter, Guy A. 2008. Inhibition of AMP-activated protein kinase protects pancreatic β-cells from cytokine-mediated apoptosis and CD8+ T-cell-induced cytotoxicity. Diabetes 57 (2) , pp. 415-423. 10.2337/db07-0993

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OBJECTIVE—Apoptotic destruction of insulin-producing pancreatic β-cells is involved in the etiology of both type 1 and type 2 diabetes. AMP-activated protein kinase (AMPK) is a sensor of cellular energy charge whose sustained activation has recently been implicated in pancreatic β-cell apoptosis and in islet cell death posttransplantation. Here, we examine the importance of β-cell AMPK in cytokine-induced apoptosis and in the cytotoxic action of CD8+ T-cells. RESEARCH DESIGN AND METHODS— Clonal MIN6 β-cells or CD1 mouse pancreatic islets were infected with recombinant adenoviruses encoding enhanced green fluorescent protein (eGFP/null), constitutively active AMPK (AMPK-CA), or dominant-negative AMPK (AMPK-DN) and exposed or not to tumor necrosis factor-α, interleukin-1β, and interferon-γ. Apoptosis was detected by monitoring the cleavage of caspase-3 and DNA fragmentation. The cytotoxic effect of CD8+ purified T-cells was examined against pancreatic islets from NOD mice infected with either null or the AMPK-DN–expressing adenoviruses. RESULTS— Exposure to cytokines, or expression of AMPK-CA, induced apoptosis in clonal MIN6 β-cells and CD1 mouse pancreatic islets. By contrast, overexpression of AMPK-DN protected against the proapoptotic effect of these agents, in part by preventing decreases in cellular ATP, and lowered the cytotoxic effect of CD8+ T-cells toward NOD mouse islets. CONCLUSIONS— Inhibition of AMPK activity enhances islet survival in the face of assault by either cytokines or T-cells. AMPK may therefore represent an interesting therapeutic target to suppress immune-mediated β-cell destruction and may increase the efficacy of islet allografts in type 1 diabetes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology
R Medicine > RC Internal medicine
Uncontrolled Keywords: AICAR, 5-amino-4-imidazolecarboxamide riboside AMPK, AMP-activated protein kinase AMPK-CA, constitutively active AMPK eGFP, enhanced green fluorescent protein IFN-γ, interferon-γ IL, interleukin KRB, Krebs Ringer bicarbonate medium TNF-α, tumor necrosis factor-α TRITC, tetramethyl rhodamine isothiocyanate TUNEL, transferase biotin dUTP nick-end labeling
Publisher: American Diabetes Association
ISSN: 0012-1797
Last Modified: 04 Jun 2017 03:59

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